Objectives

The overall aims of PRIME are to:

1) Identify and specify the molecular mechanisms underlying the insulin co-occurring diseases

2) Investigate the diseases that cause the highest-burden and costs to patients and society

3) Outline new directions for research and clinical care

We concentrate on somatic diseases type 2 diabetes, metabolic syndrome, obesity, and Romano Ward Syndrome, and their comorbidity with brain-based diseases obsessive-compulsive disorder, autism spectrum disorders, and Alzheimer’s disease. We also study the subclinical traits of these conditions that are present in the general population. In addition, we will identify currently unknown brain disorders and traits co-occurring with somatic diseases.

While the mechanisms linking insulin signaling to the somatic diseases are well-established, the insulin pathways linking somatic diseases with compulsivity disorders and Alzheimer’s disease are far from being understood. Recent work on obsessive-compulsive disorder and its symptoms in the general population suggest a shared genetic etiology with type 2 diabetes and diagnostic blood biomarkers for diabetes.

Our previous work as part of the EU FP7 TACTICS project has pointed to insulin resistance and subsequent dysregulation of synaptic function in the brain as very relevant for compulsivity-related (co)morbidity. Our work in animal models has indicated that deficits in executive functioning and learning/memory may be intermediate phenotypes between altered insulin signaling and compulsivity. In addition, neurodegenerative dementias and Alzheimer’s diseases are often thought to be linked to type 2 diabetes, metabolic syndrome and obesity through the vascular alterations associated with those disorders. However, insulin dysregulation may also more directly link to neurodegeneration in ways similar to those inducing synaptic dysfunction and cognitive impairments.

In PRIME, we hypothesize that comorbidity of type 2 diabetes, metabolic syndrome and obesity with compulsivity disorders/traits and Alzheimer’s disease, is a result of dysregulated insulin signaling.

 Our specific aims are:

• To expand our knowledge of insulin multimorbidity patterns across the lifespan and among different genders, ages and lifestyle
• To delineate the molecular and cellular causal mechanisms underlying mental and non-mental insulin multimorbidity
• To study the role of a key molecule in insulin regulation (KCNQ1)
• To identify and validate novel biomarkers
• To develop data-driven prediction models to enable early diagnosis and prediction of the prognosis
• To identify non-pharmacological preventative and treatment strategies
• To develop and test repurposed and novel pharmacological therapeutic strategies
• To outline new directions for research and clinical care of insulin co-occurring diseases
• To train practicing clinicians and a new generation of interdisciplinary researchers to be able to translate research findings into products that benefit society